Investigating the Relationship Between Insulin Processing and Senescence in β-cells
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Date
2024-07-05
Authors
Préfontaine, Camille
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Abstract
Diabetes is a chronic metabolic disease characterized by an inability to regulate blood glucose levels. The two most common forms of diabetes, type 1, and type 2, result from a loss or defects in the pancreatic β-cells which make insulin. Recent experiments demonstrate that pancreatic β-cells can undergo a poorly understood stress response, known as senescence. Previous work on human pancreatic islets shows that insulin secretion is compromised due to senescent β-cells accumulating. However, the translation of INS (gene encoding preproinsulin) precursor mRNA does not appear to change in response to senescence, suggesting that decreased insulin content may occur at the post-translational or protein level rather than at the transcriptional level. Therefore, I hypothesised that senescence in human β-cells leads to a decrease in insulin because of decreased levels of insulin synthesis enzymes prohormone convertase 1/3 (PC1/3) and
carboxypeptidase E (CPE), and increased levels of prohormone convertase 1 inhibitor (PCSK1N, hereafter referred to as ProSAAS). Both human pancreatic donor islets samples and a pure human β-cells model (EndoC-βH5), were treated with the DNA-damaging drug bleomycin to induce senescence. After bleomycin treatment, western blots were performed to evaluate the protein levels of PC1/3, prohormone convertase 2 (PC2), CPE and ProSAAS in senescent cells in comparison to vehicle controls. The western blot results showed that PC1/3 and CPE levels increased significantly in donor islets as a function of senescence. ProSAAS levels in senescence donor islets also increased significantly when compared to the control. However, the EndoC-βH5 exhibited an opposite phenotype to the donor islets, which is likely due to differences in cell maturity level and the impacts of microenvironments. These results suggest the donor islets are attempting to
compensate for the decreased insulin content by up-regulating insulin synthesis enzyme production. The upregulation of ProSAAS could serve as a potential drug target to improve b-cell function in individuals with senescent β-cell accumulation during diabetes.
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Keywords
diabetes, β-cells, beta cells, prohormone convertase 1/3, carboxypeptidase E, prohormone convertase 1 inhibitor